The major objective of this Program Project Grant is to elucidate at the molecular level the structural and functional changes in nucleic acids that occur as a result of their modification by chemical carcinogens. The carcinogens to be studied include N-2-acetylamino fluorene, benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, organochlorine pesticides and diethylstilbestrol. Nucleic acid-carcinogen complexes will be isolated from in vivo sources as well as from in vitro reactions between specific nucleic acids and activated derivatives of these carcinogens. After identification of the reactive form of specific chemical carcinogens, we shall identify the chemical structures and stereochemistry of the covalent adducts formed with nucleoside residues in RNA and DNA. We will then determine the conformational changes which occur in the nucleic acids as a result of chemical modification by these carcinogens. Finally, we will ascertain the way in which the chemical structure of the carcinogen adduct, and the associated conformational changes in the modified nucleic acid impair the function of these nucleic acids in terms of translation, transcription, replication and organization of the chromatin structure. An understanding of these early events in the process of chemical carcinogenesis could lead to the development of methods for altering host metabolic and defense mechanisms so as to prevent cancer induction. In more practical terms, an understanding of the mechanism of chemical carcinogenesis could lead to the development of more rapid and reliable methods for identifying environmental carcinogens.